Mitochondrial double-stranded RNA homeostasis depends on cell-cycle progression DOI Creative Commons

Vanessa Xavier,

Silvia Martinelli, Ryan Corbyn

et al.

Life Science Alliance, Journal Year: 2024, Volume and Issue: 7(11), P. e202402764 - e202402764

Published: Aug. 29, 2024

Mitochondrial gene expression is a compartmentalised process essential for metabolic function. The replication and transcription of mitochondrial DNA (mtDNA) take place at nucleoids, whereas the subsequent processing maturation RNA (mtRNA) mitoribosome assembly are localised to granules. bidirectional circular mtDNA can lead hybridisation polycistronic transcripts formation immunogenic double-stranded (mt-dsRNA). However, mechanisms that regulate mt-dsRNA localisation homeostasis largely unknown. With super-resolution microscopy, we show overlaps with core associated proteins granules but not nucleoids. Mt-dsRNA foci accumulate upon stimulation cell proliferation their abundance depends on ribonucleotide supply by nucleoside diphosphate kinase, NME6. Consequently, profuse in cultured cancer cells malignant human tumour biopsies. Our results establish new link between nucleic acid homeostasis.

Language: Английский

Long 3′UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation DOI
Tyler J. Dorrity, Heegwon Shin, K Wiegand

et al.

Science Immunology, Journal Year: 2023, Volume and Issue: 8(88)

Published: Oct. 20, 2023

Loss of RNA homeostasis underlies numerous neurodegenerative and neuroinflammatory diseases. However, the molecular mechanisms that trigger neuroinflammation are poorly understood. Viral double-stranded (dsRNA) triggers innate immune responses when sensed by host pattern recognition receptors (PRRs) present in all cell types. Here, we report human neurons intrinsically carry exceptionally high levels immunostimulatory dsRNAs identify long 3'UTRs as giving rise to neuronal dsRNA structures. We found neuron-enriched ELAVL family genes (

Language: Английский

Citations

37
Aicardi–Goutières syndrome: A monogenic type I interferonopathy DOI Open Access

Anran Liu,

Songcheng Ying

Scandinavian Journal of Immunology, Journal Year: 2023, Volume and Issue: 98(4)

Published: July 29, 2023

Aicardi-Goutières syndrome (AGS) is a rare monogenic autoimmune disease that primarily affects the brains of children patients. Its main clinical features include encephalatrophy, basal ganglia calcification, leukoencephalopathy, lymphocytosis and increased interferon-α (IFN-α) levels in patient's cerebrospinal fluid (CSF) serum. AGS may be caused by mutations any one nine genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11 RNU7-1) result accumulation self-nucleic acids cytoplasm or aberrant sensing acids. This triggers overproduction type I interferons (IFNs) subsequently causes AGS, prototype interferonopathies. review describes discovery history with various genotypes provides latest knowledge manifestations causative AGS. The relationship between interferonopathy potential therapeutic methods for are also discussed this review.

Language: Английский

Citations

22
Enhanced infection efficiency and cytotoxicity mediated by vpx-containing lentivirus in chimeric antigen receptor macrophage (CAR-M) DOI Creative Commons
Yun Gao,

Yue Ju,

Xiaomeng Ren

et al.

Heliyon, Journal Year: 2023, Volume and Issue: 9(12), P. e21886 - e21886

Published: Nov. 19, 2023

Genetically modified macrophage infusion has been proven to be a novel treatment for cancer. One of the most important processes in macrophage-based therapy is efficient transfer genes. HIV-1-derived lentiviruses were widely used as delivery vectors chimeric antigen receptor T and NK cell construction. While macrophages are relatively refractory this lentiviral vector transduction result myeloid-specific restriction factor SAMHD1, which inhibited virion cycle through exhausting dNTPs pool degradating RNAs. An strategy developed via packaging HIV-2 accessory protein Vpx into virion. counteracts SAMHD1 CRL4 (DCAF1) E3 ubiquitin ligase mediated degradation, yet influence by introduction on not fully evaluated. Here, we constructed HIV-1-Vpx systematically analyzed infection efficiency time-dependent manner. Our results showed that simplified virus exhibited dramatically enhanced human compared normal lentivirus. Moreover, transcriptome sequencing was performed evaluate cellular status after infection. The indicated promoted remodeling towards proinflammatory phenotype, without affecting classic M1/M2 surface markers. suggest Vpx-containing lentivirus could an ideal tool generation genetically engineered with high gene poised sets, especially solid tumor treatment.

Language: Английский

Citations

17
The RNA polymerase III–RIG-I axis in antiviral immunity and inflammation DOI Creative Commons
Leslie Naesens, Filomeen Haerynck, Michaela U. Gack

et al.

Trends in Immunology, Journal Year: 2023, Volume and Issue: 44(6), P. 435 - 449

Published: May 4, 2023

Language: Английский

Citations

15
Junctophilin-2 is a double-stranded RNA-binding protein that regulates cardiomyocyte-autonomous innate immune response DOI
Yun‐Bo Shi, Seyedsaber Mirabdali, Stefan W. Vetter

et al.

Biochemical and Biophysical Research Communications, Journal Year: 2024, Volume and Issue: 733, P. 150725 - 150725

Published: Sept. 20, 2024

Language: Английский

Citations

5
Biomolecular phase separation in stress granule assembly and virus infection DOI Creative Commons
Yi Liu,

Zhiying Yao,

Guiwei Lian

et al.

Acta Biochimica et Biophysica Sinica, Journal Year: 2023, Volume and Issue: 55(7), P. 1099 - 1118

Published: June 14, 2023

Liquid-liquid phase separation (LLPS) has emerged as a crucial mechanism for cellular compartmentalization. One prominent example of this is the stress granule. Found in various types cells, granule biomolecular condensate formed through separation. It comprises numerous RNA and RNA-binding proteins. Over past decades, substantial knowledge been gained about composition dynamics granules. SGs can regulate signaling pathways have associated with human diseases, such neurodegenerative cancer, infectious diseases. The threat viral infections continues to loom over society. Both DNA viruses depend on host cells replication. Intriguingly, many stages life cycle are closely tied metabolism cells. field condensates rapidly advanced recent times. In context, we aim summarize research granules their link infections. Notably, triggered by behave differently from canonical sodium arsenite (SA) heat shock. Studying context could offer valuable platform replication processes anti-viral responses. A deeper understanding these biological pave way innovative interventions treatments They potentially bridge gap between basic interactions hosts.

Language: Английский

Citations

13
Attenuation of reverse transcriptase facilitates SAMHD1 restriction of HIV-1 in cycling cells DOI Creative Commons

Ming-Han Tsai,

Sarah J. Caswell,

E.R. Morris

et al.

Retrovirology, Journal Year: 2023, Volume and Issue: 20(1)

Published: May 1, 2023

Abstract Background SAMHD1 is a deoxynucleotide triphosphohydrolase that restricts replication of HIV-1 in differentiated leucocytes. not restricted cycling cells and it has been proposed this due to phosphorylation at T592 these inactivating the enzymatic activity. To distinguish between theories for how but cells, we analysed effects substitutions on restriction dNTP levels both as well tetramer stability activity vitro. Results We first showed was nuclease then characterised panel mutants divided them into three classes. found subset lost their ability restrict which generally corresponded with decrease and/or Interestingly, no were able WT despite being regulated by retaining hydrolyse dNTPs. Lowering addition hydroxyurea did give rise restriction. Compellingly however, RT reduced affinity dNTPs significantly wild-type mutant U937 Jurkat T-cells. Restriction correlated reverse transcription levels. Conclusions Altogether, amino acid residue 592 strong effect formation and, although simple “on/off” switch, does correlate cells. However, preventing lowering adding enough restore Nonetheless, dNTPs, mediated observe time active capable inhibiting if reduced. This suggests very high prevents

Language: Английский

Citations

10
DNA damage response defects in hematologic malignancies: mechanistic insights and therapeutic strategies DOI
Marwan Kwok, Angelo Agathanggelou, Tatjana Stanković

et al.

Blood, Journal Year: 2024, Volume and Issue: 143(21), P. 2123 - 2144

Published: March 8, 2024

Language: Английский

Citations

3
Inhibitors of SAMHD1 Obtained from Chemical Tethering to the Guanine Antiviral Acyclovir DOI
Matthew Egleston,

Shridhar Bhat,

A. Hasan Howlader

et al.

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Sterile alpha motif histidine-aspartate domain protein 1 (SAMHD1) is an enzyme with diverse activities. Its dNTPase activity degrades all canonical dNTPs and many anticancer nucleoside drugs, while its single-stranded nucleic acid binding promotes DNA repair RNA homeostasis in cells. These functions require guanine nucleotide to a specific allosteric site (A1) on the enzyme. We previously described how activities of SAMHD1 could be inhibited vitro fragment-based inhibitor design, using dGMP as targeting fragment for A1 site. However, these dGMP-tethered inhibitors had poor cell permeability due charged monophosphate group. Here, we describe new approach where amino form acyclic acyclovir (NH2-ACV) used fragment, allowing facile coupling activated carboxylic acids (R-COOH), either directly or linkers. This generates neutral amide instead attachment points. High-throughput screening ∼375 compound library identified two compounds (8, 11) similar micromolar affinities SAMHD1. Compound 11 was obtained by direct NH2-ACV, 8 five-carbon linker. Both same dibromonaphthol component from screen. A crystal structure complex between 8, combined computational models bound 11, suggest binding. The findings establish that guanine-based do not cyclic structural elements. strategy highly amenable further chemical optimization.

Language: Английский

Citations

0
dNTP depletion and beyond: the multifaceted nature of SAMHD1-mediated viral restriction DOI Creative Commons
Pak‐Hin Hinson Cheung, Hua Yang, Li Wu

et al.

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

ABSTRACT SAMHD1 is a dNTPase of mammalian cells. In 2011, was found to be host restriction factor against retroviruses through dNTP reduction. Recent research provides evidence that the antiviral mechanisms cannot explained solely by its activity. Instead, versatility SAMHD1-mediated various viruses suggests extend beyond depletion. This explains multifaceted and broad functions play significant role in innate immunity.

Language: Английский

Citations

0